The impact of APOE genotype, age, and sex on gut microbiota in a mouse model of Alzheimer's Disease: an exploration of their interactions.

BACKGROUND: As an important interface between the peripheral environment and the central nervous system, the gut microbiota varies greatly between patients or animals with Alzheimer's disease (AD) and their respective non-AD counterparts; however, it remains unexplored whether the apolipoprotein E (APOE) genotype, age, and sex may interactively influence the characteristics of gut microbiota in AD animals. METHODS: APOE genotype, age, and sex were enrolled as independent variables, with genotype distinguished into APOE3 and APOE4, age into 3 and 10 months, and sex into female and male. The composition, structure, and potential functions of gut microbiota were systematically analyzed by 16S rRNA gene amplicon sequencing to evaluate the individual and interactive effects of APOE genotype, age and sex. RESULTS: Significant interactions were observed among APOE genotypes, ages, and sexes, with different factor combinations exhibiting distinct effect on microbiotic composition and functional potential. APOE genotype exerted the most significant influence on gut microbiota, followed by age and sex with a relatively minor effect, highlighting the dominant role of host genetic background. Functional prediction analysis indicated that the functional profiles were mainly concentrated in basic metabolic pathways, including the biosynthesis of secondary metabolites and amino acids, and carbon metabolism. CONCLUSION: APOE genotype, age, and sex are jointly associated with the structure and potential function of the gut microbiota in AD model mice. These findings provide a perspective of multi-factor interaction into the alterations in gut microbiota in AD and offer new microecological evidence for understanding APOE4-related AD susceptibility, as well as a conceptual basis for future stratified microecological intervention studies. Alzheimer’s disease (AD) is a common brain disorder that causes various cognitive problems, especially in elderly adults. The APOE gene may affect a person’s risk of developing AD, with one form of this gene (APOE4) indicating a higher risk. Meanwhile, growing evidence suggests that the bacteria living in our gut may influence brain health. However, it remains unclear how genetic background, age, and biological sex work together to shape gut bacteria in AD.This study used mice of both sexes with different APOE genetypes (APOE3 or APOE4) at different ages to examine the types of gut bacteria present and their potential biological functions. We found that rather than acting alone, these factors showed combined effects on the composition and potential activity of gut bacteria. Different combinations of genetype, age, and sex were associated with distinct gut microbiota patterns. We also found that the predicted functions of gut bacteria varied across these groups, especially in processes related to basic metabolism. These results suggest that genetic risk, age, and sex together shape the gut environment in ways that may be relevant to AD vulnerability.The findings highlight the importance of considering age and sex when studying genetic risk for AD and suggest that future gut-targeted prevention or intervention strategies may need to be tailored to individual biological backgrounds.